Genetic Testing Trifecta Predicts Risk of Sudden Cardiac Death and Arrhythmia

Arrhythmias such as atrial fibrillation and sudden cardiac death can develop with few early symptoms, exposing patients to serious complications before treatment begins. Existing genetic tests capture only part of a person’s inherited risk, limiting their clinical utility. A new study has introduced a more precise genetic risk score that combines rare variants, common variants, and whole-genome data to better predict who is most likely to develop arrhythmias.

The approach, developed by researchers at Northwestern University Feinberg School of Medicine (Chicago, IL, USA), integrates all three major genomic testing methods, offering a unified framework capable of detecting rare mutations, summing the influence of common risk variants, and analyzing the full non-coding genome for hidden regulatory signals. This combined analysis produced a more complete genetic picture than currently available testing.

Using whole-genome sequencing, the researchers examined genetic data from 523 participants with confirmed arrhythmias — some also living with heart failure — and rigorously validated each case through clinical records and device-captured data. They then compared these genomic findings with those of 596 control participants aged 40 and older from a biobank who had no history of cardiac disease. Rare variant data, polygenic scores, and genome-wide features were integrated to calculate individualized risk scores.

The combined framework enabled the researchers to identify individuals at the highest risk with a substantially improved odds ratio compared to any single genetic method. The findings, published in Cell Reports Medicine, also underscore the potential for targeted therapies informed by a patient’s full genetic profile. Clinicians could detect risk before symptoms appear, support decisions regarding monitoring strategies, and determine whether preventive measures such as defibrillator placement are warranted.

This unified approach also highlights the need for greater adoption of genetic testing in cardiology. Despite its value, only a small fraction of eligible patients currently undergo testing. Expanding physician training and awareness may allow these risk-stratification tools to influence clinical care more widely.

“It’s a very cool approach in which we are combining rare gene variants with common gene variants and then adding in non-coding genome information,” said co-corresponding author Dr. Elizabeth McNally. “To our knowledge, no one has used this comprehensive approach before, so it’s really a roadmap of how to do that.”

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Northwestern University Feinberg School of Medicine